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2Department of Biostatistics and the Center for Biostatistics in AIDS Research, Harvard T H Chan School of Public Health, Boston, MA, USA

3Program On Regulation, Therapeutics, And Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA

Correspondence to: J H Powers jpowers3@aol.com

Current approaches to testing new treatments for multidrug resistant bacterial diseases raise scientific and ethical issues for current and future patients, say John Powers and colleagues

Concerns over the threat of antibiotic resistance have fuelled legislative and regulatory efforts to promote development of new treatments for serious infections. Fears arise that the world could face serious, multidrug resistant bacterial diseases that lack effective treatments. An optimal approach would be to develop drugs that improve on current effective therapies for today’s patients, while potentially offering benefits for future patients as antibiotic resistance evolves.

Unlike in many other therapeutic areas, however, most new antibiotics are approved without evidence of superior efficacy in clinical trials. Rather, regulatory authorities increasingly permit “non-inferiority” hypotheses. These allow lesser effectiveness than already approved drugs in trade-off for other benefits such as decreased adverse effects.12345 Indeed, some claim that superiority hypotheses are unethical for investigational antibiotics since they might expose patients in the control group to harm.6

A review evaluating US Food and Drug Administration approvals from 2009 to 2015 showed eight new antibiotics indicated for “serious and life threatening” diseases, with seven approved solely on evidence of non-inferiority. Recent FDA guidance supports extrapolating non-inferiority results in patients with effective treatments to presume superior outcomes in patients without effective options.25 But are drugs that are “non-inferior” today going to be superior tomorrow? Do non-inferiority hypotheses expose today’s patients with treatable life threatening infections to increased risk of harm by allowing investigational antibiotics with less effectiveness onto the market?

Multidrug resistance and development of new antibiotics

Although resistant infections have been commonplace since the advent of antibiotics in the 1940s, effective treatment still remains for most patients. Resistance should be of most concern when the drugs show decreased effects on morbidity and mortality. However, discussions about the rise …